The aims of this proposal remain to provide an understanding in molecular terms of the interactions between sensitized lymphocytes and macrophages which lead to the various manifestations of cell-mediated immune reactions. The focus of the present application is the biochemical mechanisms by which macrophages, particularly "activated" macrophages, carry out various effector functions. Experiments are proposed to investigate the nature of macrophage immunoglobulin and complement receptors, the mechanisms underlying phagocytosis, migration and secretion of lysosomal hydrolases and neutral proteases, molecular mechanisms of extracellular killing of tumor cells and intracellular killing of ingested parasites, as well as mechanisms of macrophage mediated tissue damage associated with cell-mediated immune reactions. A major goal is to understand the regulation of these phenomena, as by products of activated lymphocytes, such as MIF, pharmacologic and hormonal agents. Our approach is to use cloned homogeneous macrophage cell lines as a useful model for studying many of these questions, and to develop somatic cell variants and mutants defective in various steps of the different individual macrophage functions. By understanding the nature of the individual genetic and biochemical lesions it may be possible to piece together the complex molecular steps which give rise to macrophage effector functions.